Malignant glioma ranks among the least curable of human cancer despite aggressive surgery, radiation therapy, chemotherapy, and the emergence of new targeted molecular therapeutics. This unresponsiveness to current therapeutics stems to a great degree from the innate resistance of malignant glioma cells to a broad range of cytotoxic agents. During our initial funding period, we identified pre- and post-transcriptional mechanisms by which SF/HGF, a multifunctional growth factor overexpressed by human malignant gliomas, protects glioma cells against genotoxic agents. We showed that targeting SF/HGF in vivo induces glioma cell death, sensitizes glioma to radiation therapy, and markedly prolongs the survival of animals bearing SF/HGF- expressing brain tumors. These exciting discoveries contributed to the biological rationale for newly activated and planned clinical trials testing SF/HGF:c-Met pathway inhibitors in glioblastoma multiforme. The continued goals of this ambitious and collaborative research program are to identify biochemical and molecular mechanisms of glioma resistance to cytotoxicity and to further develop novel and potentially translatable strategies for overcoming resistance to death-inducing agents. Death receptor agonists (TRAIL, FASL) are promising anti-tumor agents by virtue of their ability to selectively kill tumor cells. We have identified novel strategies (e.g. anisomycin-induce ribotoxic stress) for sensitizing glioma cells to death receptor agonists. In Aim #1 we will determine the mechanisms by which genotoxic and ribotoxic stresses induce DISC (death- initiating signaling complex) formation and caspase-8 activation. In Aim #2 we will determine mechanisms by which SF/HGF and other receptor tyrosine kinase pathways protect glioma cells against death receptor agonists. In contrast to kinases, little is known of how phosphatases contribute to oncogenic signaling cascades. We found that two SH2-containing inositol-5-phosphatases (SHIP1 and SHIP2) regulate glioma cell sensitivity to chemotherapeutics. In Aim #3 we will determine the mechanisms by which these lipid phosphatases modulate glioma cell death. In Aim #4 we will apply the novel death modulating strategies of Aims #1-3 to enhance anti-tumor responses to cytotoxic therapeutics (death receptor agonists, chemotherapy, and radiation therapy) in pre-clinical in vivo glioma models. The successful completion of these experiments will reveal novel mechanisms for enhancing glioma cell death and provide pre-clinical evidence supporting their therapeutic applicability. PUBLIC HEALTH RELEVANCE: Glioblastoma multiforme, the most common and aggressive brain tumor in adults, has a median life expectancy of ~ 14 mo and fewer that 30% of patients are alive 2 years after diagnosis. These dismal responses to aggressive therapy are due to the innate resistance of glioma cells to current cytotoxic treatments. This research plan will identify molecular/biochemical approaches for overcoming glioma cell resistance to cytotoxic agents and test their therapeutic applicability in vivo.